Lung cancer is the leading cause of cancer-related Deaths world wide with 1.2 million new cases diagnosed every year and with 1 million deaths being recorded worldwide in 2001. Lung cancer is divided into two main groups, small cell lung cancer and non-small cell lung cancer. Approximately 75%-85% of these patients have non small cell lung cancer and rest have small cell lung cancer. Non small cell lung cancer (NSCLC) has been further classified as per histology into a number of different types, including inter alia adenocarcinoma, squamous cell carcinoma and large cell carcinoma adenocarcinoma are often found in an outer area of the lung. Squamous cell carcinomas are usually found in the center of the lung next to an air tube (bronchus). Large cell carcinomas can occur in any part of the lung. They tend to grow and spread faster than the other two types.
Immunohistochemistry (IHC) refers to the process of detecting molecules in cells of a tissue section by exploiting the principle of antibodies binding specifically to molecules in biological tissues. Immunohistochemical staining is widely used in the diagnosis of abnormal cells such as those found in cancerous tumors.
IHC is also widely used in basic research to understand the distribution and localization of biomarkers and differentially expressed proteins in different parts of a biological tissue.
Desmocollin-3 is expressed in squamous variety of NSCLC and its presence, as detected for example by IHC, is typically used to differentiate squamous cell carcinoma from Adenocarcinoma. Thyroid transcription factor 1 (TTF-1) is expressed in Adenocarcinoma of the Lung and its presence, as detected for example by IHC, is typically used to differentiate Adenocarcinoma from Squamous cell carcinoma. The basis of Immunohistochemistry is to detect presence of expression of a particular biomarker. Desmocollin-3 and TTF-1 are such biomarkers which are specific for Squamous cell carcinoma and Adenocarcinoma of the Lung respectively. TTF-1 is a protein that regulates the transcription of genes. Desmocollin-3 belongs to the Cadherin group of cell adhesion molecules. Desmocollins are calcium dependent adhesion molecules. Desmocollin 1, 2 and 3, are desmosomal component typically found in pseudostratified and stratified epithelia. Desmocollin-3 is expressed on basal most layers of stratified epithelia and its expression decreases gradually in the suprabasal layers. The expression of RNA specific to desmocollin gene is associated with the expression of desmocollins. It has been observed that cells containing a specific desmocollin subtype tend to cluster together to the exclusion of other types.
Historically, first-line treatment for patients with advanced NSCLC has been platinum-based doublet chemotherapy in combination with a third-generation cytotoxic compound such as gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis, Ind.), Paclitaxel (Taxol; Bristol-Myers Squibb, Princeton, N.J.) or Docetaxel (Taxotere; Sanofi-Aventis, Bridgewater, N.J.). Clinical trials of a platinum based therapy in combination with any of these agents demonstrated comparable efficacy, and meta-analyses showed that these regimens offered superior survival and symptom palliation versus best supportive care. The study conducted by Eastern Cooperative Oncology Group (ECOG) comparing four platin-based, two-drug chemotherapy regimens in more than 1100 patients suggests no significant differences in overall survival among the groups.
The first line therapy is offered irrespective of histology of the tumor. The efforts are made to improve the out come of first line therapy without any success.
Recently Bevacizumab is approved as add on therapy to first line therapy for non squamous cell lung cancer. Bevacizumab has been demonstrated in combination with first line therapy to improve outcomes over those seen with first line therapy alone in the treatment of advanced non squamous NSCLC. The two large, phase III, randomized trials leading to these relevant results have administered bevacizumab with carboplatin plus paclitaxel and cisplatin plus gemcitabine as first line therapy
Similarly it is also observed that pemetrexed is useful in non squamous carcinoma of lung. Non squamous patients treated with pemetrexed-based therapy experienced longer survival than the comparators (HR, 0.78 and 0.84 respectively), whereas squamous patients had shorter survival (HR, 1.56 and 1.23 respectively). It is recommended that it should not be used in squamous cell carcinoma of lung as it worsens the prognosis.
Thus, histology of tumor plays significant role in improvement with first line therapy by addition of a new drug. IHC helps in defining characteristics of cell types and also deciding histology subtype of a tumor as it helps in choosing appropriate therapy.
There is a significant improvement in outcome of non squamous lung cancer recently but no further improvement is seen in patients suffering from squamous cell carcinoma.
Immune surveillance of body is responsible for eliminating cancer cells before they manifest as tumor. Tumor growth is associated with escape from immune surveillance due to immune suppression by tumor or other causes. Immuno-suppression is known to be proportional to size of a tumor. Immunotherapy helps in reconstituting immunity.
Immunotherapy may result in a robust reconstitution of immunity which is able to overcome existing immuno-suppression under such circumstances tumor is eliminated. Initially this will manifest as regression of a tumor. This is typically observed when tumor burden is small. In case immune response generated is not adequate to overcome immuno-suppression but achieves equilibrium with immuno-suppression, tumor doesn't grow in size but remains stationary. There is improvement in survival in absence of tumor response.
Immunotherapy may be used alone or in combination of other cancer therapies for cancer.
In all the figures the test arm is having better survival compared to central arm. The test arm is having higher value as survival at end of study period compared to control arm.